Proto-oncogenes are normal genes that can become oncogenes following mutations. They encode proteins involved in cell growth, proliferation, differentiation and apoptosis. Examples include HER2, Wnt, Myc, Ras and genes in the Ras signaling pathway. Mutations in proto-oncogenes convert them into oncogenes, driving uncontrolled cell growth and tumor development. Common mutations are point mutations, which result in overactive gene products by altering transcription or protein function. For example, point mutations in Ras genes are found in many cancers and keep the Ras protein constantly active.

1. Proto-oncogene
• The genes that involve in the cancer can be divided into following
types. Proto-oncogenes Proteins encoded by proto-oncogenes may
function as growth factors or their receptors, signal transducers,
transcription factors, or cell cycle components. Proto Oncogenes
products regulate the cell growth, division of cells, prevent cell
differentiation and regulate apoptosis.

2. Examples of Proto oncogenes is the Her2 gene. This gene codes for a
transmembrane tyrosine kinase receptor called Human epidermal growth
factor receptor. This protein receptor is involved in the growth repair and
division of cell in the breast. Wnt, Myc, Fos/Jun, RTK, Ras MAP kinase are
Proto oncogenes.
Products of proto oncogenes genes are essential for cell survival and
growth. Mutations in proto-oncogenes convert proto-oncogenes into
constitutively active cellular oncogenes that are involved in tumor
development.

3. Protooncogenes convert it into oncogenes by the following type of mutation Point mutation: a
protooncogene is convert into oncogene by insertions or deletions that give rise overactive gene
product. This mutation also leads to an increase in transcription rate.
For example, a change in 'ras' oncogene includes H-ras, K-ras, and N-ras. The proto-oncogene
code for signal transduction. A GTP-binding protein has GTPase activity that become active to
inactive by hydrolysis of GTP to GDP.
The RAS genes, of which there are three in the human genome (HRAS, KRAS, NRAS), were
discovered initially in transforming retroviruses. The single most common abnormality of proto-
oncogenes in human tumours is Point mutation of RAS family genes.

4. When RAS is bounded
with GDP it is inactive
when RAS is bounded with GTP it is active. The
activated RAS stimulates downstream regulators
of proliferation, such as the mitogen-activated
protein (MAP) kinase cascade
GTP hydrolysis, which converts
the GTP-bound, active RAS to the
GDP-bound, inactive form.
Guanine nucleotide
exchange factors turn
on signalling by
catalysing
GAPs terminate signalling
by inducing GTP hydrolysis.
GDP
GDP
GTP
GTP
GDPGTP
GEFGAP
Gα Gβ
Gγ
Gα Gβ
Gγ
Gα
Gβ
Gγ
Gα Gβ
Gγ

5. Several different point mutations of RAS have been identified in cancer
cells. The point mutation reduce the GTPase activity of the RAS protein,
thus cell is forced into a continuously proliferating state. In Colon, lung and
pancreatic tumors point mutation is found in KRAS. In Bladder and Kidney
tumors point mutation is found in HRAS. In Melanomas tumors point
mutation is found in NRAS and in BRAF. In Hepatoblastoma, hepatocellular
carcinoma tumors point mutation causes overexpression of b-catenin. b-
catenin is involved in WNT signal transduction. In Acute lymphoblastic
leukemia ABL is translocated. ABL is a Nonreceptor tyrosine kinase.

6. Protein
Biosynthesis
MicroRNAs
Cell
adhesion
DNA repair
Translation
Metabolism
Cell Cycle
Signal
Transduction
Transcription

7. Myc (c-Myc) is a regulator gene that codes for a transcription factor. Play
important role in cell cycle, apoptosis and cellular transformation.
In Burkitt lymphoma, a B-cell tumor the Myc gene is translocate to Burkitt
lymphoma, a reciprocal translocation between chromosomes 14 and 18 is also
extremely common in follicular B cell lymphoma.
Fusion of the BCL-2 gene with the IGH locus, resulting in
anti-apoptotic protein BCL-2 overexpression.
MYC is amplified in some cases of breast, colon, lung, and
many other carcinomas. The related N-MYC and L-MYC
genes are amplified in neuroblastomas and small-cell
cancers of the lung,
Dysregulation of MYC expression resulting from translocation
of the gene occurs in Burkitt lymphoma, a B-cell tumor.
Diffuse large
B-cell lymphoma
Burkitt
lymphoma
Mantle cell
lymphoma
Follicular
lymphoma
C-3,14
C-8,14 C-11,14 C-18,14